The primary objective of this proposal is to develop and commercialize a safe and more effective therapy for the treatment of Crohn's Disease, an inflammatory bowel disease. Crohn's Disease is a chronic inflammatory disorder of the gastrointestinal tract that affects some 500,000 patients in the US. Selexys Pharmaceuticals is developing a fully human anti-PSGL-1 antibody drug directed against P-selectin glycoprotein ligand-1 (PSGL-1), a dimeric mucin on circulating leukocytes that binds selectins and chemokines, for the treatment of Crohn's Disease. PSGL-1 mediates the first step in the recruitment of leukocytes to sites of inflammation by binding to selectins, cell adhesion molecules that are upregulated in Crohn's Disease patients. PSGL-1 also binds chemokines that amplify the inflammatory response through chemotaxis of inflammatory cells to endothelial cells that line the gut. In preclinical studies in animal models of Crohn's Disease, anti-PSGL-1 antibodies have been shown to block recruitment of leukocytes resulting in a profound therapeutic effect. Thus anti-PSGL-1 antibodies represent a novel new potential therapeutic approach in the treatment of Crohn's Disease. In Phase 1 of this Fast Track Proposal, Selexys is proposing to conduct primate safety and toxicity studies in cynomolgus monkey with a human anti-PSGL-1 IgG2 antibody that has been engineered to lack effector function and complement binding. Pharmacokinetic (PK), pharmacodynamic (PD) and immunogenicity bioassays in support of this proposal are currently being developed by Selexys. Manufacture of drug substance to support the proposed preclinical studies and clinical trials is underway at Cytovance Biologics in Oklahoma City. Selexys is proposing to conduct a PK pilot dose ranging study in cynomolgus monkey (Macaca fascicularis) to assess safety and PK of the anti-PSGL-1 antibody. The pilot study will guide dosing plans to conduct an IND enabling 4-week IV repeat dose toxicity study in cynomolgus monkey. In Phase 2 of this application Selexys proposes to conduct a Phase I safety study in healthy volunteers leading to a Phase IIa safety and efficacy trial in Crohn's Disease patients. The primary goal of the proposed study is to characterize the antibody prior to commencing a Phase IIb six months chronic dosing trial. The overarching goal of the program is to develop and commercialize a humanized antibody to PSGL- 1 to treat Crohn's Disease patients. In doing so Selexys will address an inflammatory bowel disease with major unmet medical needs with a therapy that may be safer than current approved biologic therapies and that has the potential to sustain remission and/or ameliorate the devastating effects of this disease. PUBLIC HEALTH RELEVANCE: This proposal supports development of a fully human antibody to PSGL-1 to treat Crohn's Disease patients. Crohn's Disease is an inflammatory bowel disease that affects 500,000 persons in the U.S. The drug being developed addresses a major unmet medical need for a therapy that can maintain remission and/or ameliorate the devastating effects of this disease.